ES2874573T3 - Crystal modifications of elobixibat - Google Patents

Abstract

Crystalline anhydrate F of elobixibat, having an XRPD pattern, obtained with CuKα1 radiation, with peaks at positions °2θ 6.1 ± 0.2 and 5.9 ± 0.2.

Description

DESCRIPTION

Crystal modifications of elobixibat

The present invention relates to crystal modifications of W - {(2R) -2 - [({[3,3-dibutyl-7- (methylthio) -1,1-dioxide-5-phenyl-2,3,4, 5-tetrahydro-1,5-benzothiazepin-8-yl] oxy} acetyl) amino] -2-phenylethanolyl} -glycine (elobixibat).

Background

WO 02/50051 describes the compound 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -1'-phenyl-1 '- [W- (carboxymethyl) -carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine (elobixibat; IUPAC name: W - {(2R) -2 - [({[3,3-dibutyl -7- (methylthio) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl] oxy} acetyl) amino] -2-phenylethanolyl} glycine) . This compound is an inhibitor of ileal bile acid transporter (ileal bile acid transporter - IBAT), which can be used in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes and liver diseases. According to the experimental section of document WO 02/50051, the last synthesis step in the preparation of elobixibat consists in the hydrolysis of a tert-butoxylic ester under acidic conditions. The crude compound was obtained by evaporation of the reaction mixture under reduced pressure and purification of the residue by preparative HPLC using acetonitrile / ammonium acetate buffer (50:50) as eluent (Example 43). After lyophilizing the product, no crystalline material was identified.

It would be desirable to discover forms of elobixibat that are robust enough to be suitable for formulation as a pharmaceutical.

Various crystal modifications can have disadvantages including residual solvents, a varying degree of crystallinity, and difficulties in handling and formulation. Therefore, there is a need for crystal modifications of elobixibat that have improved properties with respect to stability, bulk handling, and solubility. Therefore, it is an object of the present invention to provide a stable crystalline modification of elobixibat with good crystallinity and other formulation properties.

Summary of the invention

The invention provides various crystal modifications of elobixibat. The present invention is based in part on the discovery that elobixibat tends to form highly crystalline solvated structures with many solvents. As seen in the examples below, several of the crystal modifications form crystalline ansolvates when the solvent is removed from the crystal. Several of these crystals can then form hydrates, after exposure to a sufficiently humid environment. It is surprising that these crystal modifications contain a substantially stoichiometric amount of solvate in view of their ability to lose and recover solvate molecules without dissolution or recrystallization.

In one aspect, the crystalline modification is a crystalline form of elobixibat that is capable of or actually contains a substantially stoichiometric amount of water. Preferably, the substantially stoichiometric amount of water is not one mole per mole of elobixibat. A substantially stoichiometric amount of water is an amount that is within 15 mole% of an integer value. Thus, for example, a dihydrate includes 1.7-2.3 moles of water associated with each mole of elobixibat in a crystal. The amount of water calculated in the present description excludes water adsorbed on the glass surface. The invention further includes elobixibat anhydrates.

The invention further provides the use of the crystal modifications described in the present description in the treatment of a condition described in the present description.

Brief description of the figures

Fig. 1 shows the X-ray powder diffractogram of crystal modification F produced from methyl isobutyl ketone.

Fig. 2 shows the X-ray powder diffractogram of crystal modification F produced from ethyl acetate.

Fig. 3 shows the X-ray powder diffractogram of crystal modification C produced from acetone: water 1: 1 v / v.

Fig. 4 shows the X-ray powder diffractogram of crystal modification C produced from ethyl acetate.

Fig. 5 shows the powder X-ray diffractogram of crystal modification L.

el difractograma de rayos X de polvos de la modificación cristalina N.Fig. 6 shows

X-ray powder diffractogram of crystal modification N.

el difractograma de rayos X de polvos de la modificación cristalina E.Fig. 7 shows

X-ray powder diffractogram of crystal modification E.

el difractograma de rayos X de polvos de la modificación cristalina G.Fig. 8 shows

X-ray powder diffractogram of crystal modification G.

el difractograma de rayos X de polvos de la modificación cristalina H.Fig. 9 shows

X-ray powder diffractogram of crystal modification H.

Fig. 10 shows the DVS isotherm plot of crystal modification F. The four curves show sorption and desorption for two consecutive DVS cycles. The x-axis shows the% RH change and the y-axis shows the sample response in wt% water.

Fig. 11 shows the DVS isotherm plot of crystalline modifications C and E. The four curves show sorption and desorption for two consecutive DVS cycles. The x-axis shows the% RH change and the y-axis shows the sample response in wt% water.

Fig. 12 shows the powder X-ray diffractogram of crystal modification D.

Fig. 13 shows the powder X-ray diffractogram of crystal modification M.

Fig. 14 shows the DVS isotherm plot of the L and N crystal modification. The four curves show sorption and desorption for two consecutive DVS cycles. The x-axis shows the% RH change and the y-axis shows the sample response in wt% water.

Fig. 15 shows a conversion diagram for several of the crystal modifications described in the present disclosure.

Detailed description of the invention

The invention described in the present description relates to crystal modifications that were discovered in extensive studies on elobixibat. Without wishing to be bound by theory, it is believed that crystalline forms of elobixibat can be formed from a variety of solvents that possess at least some polar character. Again, without wishing to be bound by theory, it is believed that elobixibat forms crystalline structures containing occupied or partially occupied void volumes, where the solvent molecules reside. Voids are unusual in many of these crystals in that they maintain a substantially stoichiometric amount of solvate molecules (eg, hydrate), however, the solvate molecules can be removed and replaced without dissolution or recrystallization of the crystals. It is advantageous to contain substantially stoichiometric amounts of water, since the water content of the crystals remains substantially constant even with changes in relative humidity. In certain embodiments, the water content remains substantially constant at RH greater than 20%, 30%, 40% or more. In other embodiments, the water content remains substantially constant at RH less than 20% or 10%.

In one aspect, the invention relates to a crystalline form of elobixibat, where the form includes void volumes that are capable of containing a substantially stoichiometric amount of water, such as under conditions of 10% RH and 20 ° C, 40% of RH and 20 ° C, 58% RH and 20 ° C, 80% RH and 20 ° C, or 75% RH and 40 ° C. The invention includes both the hydrate and anhydrate forms of the relevant crystals. Preferably, the substantially stoichiometric amount of water is not one mole per mole of elobixibat (eg 0.7-1.3 mole, 0.8-1.2 mole, or 0.9-1.1 mole of water per mole of elobixibat). A substantially stoichiometric amount of water is an amount that is within 15 mole% (eg, 10 mole%, 5 mole%, 2.5 mole%) of an integer value. Thus, for example, a dihydrate includes 1.7-2.3, 1.8-2.2, 1.9-2.1 or 1.95 2.05 moles of water associated with each mole of elobixibat in a crystal . For an anhydrate, there are less than 0.15 moles, less than 0.10 moles, or even less than 0.05 or 0.025 moles associated with each mole of elobixibat. The amount of water calculated in the present description excludes water adsorbed on the glass surface. Void volumes, as used in the present description, refer to more or less isolated channels, layers or voids in the crystal structure.

In certain embodiments, the invention includes a crystalline elobixibat anhydrate, where the anhydrate is stable at a relative humidity (RH) of 10% or less or 20% or less at a temperature of 20 ° C. Said anhydrate can be stable under these conditions for at least 1 hour, 1 day, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years or more. It is advantageous that certain anhydrates are stable during these periods under different storage conditions, such as 40% RH and 20 ° C, 58% RH and 20 ° C, 80% RH and 20 ° C, or 75% of HR and 40 0C. Anhydrates stable at 10% RH (eg 20 ° C or 40 ° C) are particularly suitable for Zone III conditions (hot / dry) or in formulations containing drying agents (eg gel silica, calcium sulfate, calcium chloride, calcium phosphate, sodium chloride, sodium bicarbonate, sodium sulfate, sodium phosphate, montmorillonite, molecular sieves (beads or powder), alumina, titania, zirconia, and sodium pyrophosphate), while anhydrates stable at RH 40% and above are suitable for Zone I (temperate), II (subtropical), and IV (hot / humid) conditions.

Stability can be evaluated as physical stability, chemical stability, or both. Chemical stability refers to the molecule (i.e. elobixibat) that does not undergo reaction to a new molecule. Physical stability refers to the fact that the crystal structure does not change over time, which can be measured by one or more of the techniques described in the present description, such as XPRD, and optionally complemented with DVS, TGA and DSC.

In one embodiment, the crystalline anhydrate is a crystalline modification F that has an X-ray powder diffraction pattern, obtained with CuKa1 radiation, with at least specific peaks at 296 positions, 1 ± 0.2 and / or 5.9 ± 0.2. In certain embodiments, the invention relates to the crystal modification F having an XRPD pattern, obtained with CuKa1 radiation, with specific peaks at positions ° 296.1 ± 0.2 and 5.9 ± 0.2 and one or more of the characteristic peaks: 6.6 ± 0.2, 8.3 ± 0.2 and 11.9 ± 0.2. In a more particular embodiment, the invention refers to the crystalline modification F that has an XRPD pattern, obtained with CuKa1 radiation, with specific peaks at positions ° 29 6.1 ± 0.2, 5.9 ± 0, 2, 6.6 ± 0.2, 8.3 ± 0.2 and 11.9 ± 0.2. In another embodiment, the invention refers to the crystalline modification F that has an XRPD pattern, obtained with CuKa1 radiation, with characteristic peaks at positions ° 296.1 ± 0.2, 5.9 ± 0.2, 6 , 6 ± 0.2, 8.3 ± 0.2 and 11.9 ± 0.2, and one or more of 7.4 ± 0.2, 10.6 ± 0.2, 11.7 ± 0.2, 19.2 ± 0.2 and 19.8 ± 0.2. In an even more particular embodiment, the invention relates to the crystalline modification F having an XRPD pattern, obtained with CuKa1 radiation, substantially as shown in Figure 1 or Figure 2.

In one embodiment, the crystalline anhydrate is a C crystalline modification that has an X-ray powder diffraction pattern, obtained with CuKa1 radiation, with at least specific peaks at 2912 ° positions, 4 ± 0.2 and / or 5.8 ± 0.2. In certain embodiments, the invention relates to crystalline modification C having an XRPD pattern, obtained with CuKa1 radiation, with specific peaks at positions ° 2912.4 ± 0.2 and 5.8 ± 0.2 and one or more of the characteristic peaks: 4.8 ± 0.2, 8.2 ± 0.2, 9.9 ± 0.2, 10.9 ± 0.2, 16.6 ± 0.2, 19.8 ± 0.2 and 20.6 ± 0.2. In a more particular embodiment, the invention refers to crystalline modification C that has an XRPD pattern, obtained with CuKa1 radiation, with specific peaks at positions ° 2912.4 ± 0.2, 5.8 ± 0.2 , 4.8 ± 0.2, 8.2 ± 0.2, 9.9 ± 0.2, 10.9 ± 0.2, 16.6 ± 0.2, 19.8 ± 0.2 and 20 , 6 ± 0.2. In another embodiment, the present invention refers to the crystalline modification C that has an XRPD pattern, obtained with CuKa1 radiation, with characteristic peaks at positions ° 2912.4 ± 0.2, 5.8 ± 0.2, 4.8 ± 0.2, 8.2 ± 0.2, 9.9 ± 0.2, 10.9 ± 0.2, 16.6 ± 0.2, 19.8 ± 0.2 and 20, 6 ± 0.2, and one or more of 4.1 ± 0.2, 6.7 ± 0.2, 9.5 ± 0.2, 12.6 ± 0.2, and 20.7 ± 0.2 . In an even more particular embodiment, the invention relates to the crystalline modification C having an XRPD pattern, obtained with CuKa1 radiation, substantially as shown in Figure 3 or Figure 4.

In one embodiment, the crystalline anhydrate is an L crystalline modification that has an X-ray powder diffraction pattern, obtained with CuKa1 radiation, with at least specific peaks at 296 positions, 4 ± 0.2 and / or 12.7 ± 0.2. In certain embodiments, the invention relates to the L crystal modification having an XRPD pattern, obtained with CuKa1 radiation, with specific peaks at positions ° 296.4 ± 0.2 and 12.7 ± 0.2 and one or more of the characteristic peaks: 4.2 ± 0.2, 8.5 ± 0.2, 10.5 ± 0.2, 19.3 ± 0.2 and 19.5 ± 0.2. In a more particular embodiment, the present invention refers to the L crystalline modification that has an XRPD pattern, obtained with CuKa1 radiation, with specific peaks at positions ° 296.4 ± 0.2, 12.7 ± 0, 2, 4.2 ± 0.2, 8.5 ± 0.2, 10.5 ± 0.2, 19.3 ± 0.2, and 19.5 ± 0.2. In another embodiment, the present invention refers to the L crystalline modification that has an XRPD pattern, obtained with CuKa1 radiation, with characteristic peaks at positions ° 296.4 ± 0.2, 12.7 ± 0.2, 4.2 ± 0.2, 8.5 ± 0.2, 10.5 ± 0.2, 19.3 ± 0.2 and 19.5 ± 0.2, and one or more than 4.8 ± 0 , 2, 5.9 ± 0.2, 12.1 ± 0.2, 12.4 ± 0.2, 13.3 ± 0.2, 13.6 ± 0.2, 17.7 ± 0.2 , 19.9 ± 0.2 and 21.4 ± 0.2. In an even more particular embodiment, the invention relates to the L crystal modification having an XRPD pattern, obtained with CuKa1 radiation, substantially as shown in Figure 5.

In a second aspect, the invention includes a crystalline elobixibat dihydrate. Preferably, the dihydrate includes 1.7-2.3, 1.8-2.2, 1.9-2.1 or 1.95-2.05 moles of water associated with one crystal per mole of elobixibat. The amount of water calculated in the present description excludes water adsorbed on the glass surface.

In one embodiment, the dihydrate is stable when in contact with water (eg, a solution where water is the solvent). Said dihydrates can be, in addition or alternatively, stable in a saturated or near saturated atmosphere (ie 90%, 95%, 100% RH). Said dihydrates can be stable at temperatures of 20 ° C, 40 ° C, 60 ° C or even 75 ° C. Stability can exist for a period of 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, or more. In certain embodiments, the dihydrate is also stable at RH as low as 60%, 40%, or even 20% for periods of 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years. , 3 years or more, at temperatures of 20 0C, 40 0C, 60 0C or even 75 0C.

In another embodiment, which may have a stability as indicated above, a dihydrate may be crystallized directly from the suspension. In certain embodiments, crystallization can occur after elobixibat synthesis without purification. Illustrative conditions include crystallization with 1: 1 volume mixtures of methanol or 2-propanol and water at 50C. The advantages of such direct crystallization they include easier purification and less difficult separation, with less associated risk of residual solvents.

In one embodiment, the crystalline dihydrate is an E crystalline modification that has an X-ray powder diffraction pattern, obtained with CuKa1 radiation, with at least specific peaks at positions o206,1 ± 0.2 and / or 12.0 ± 0.4.

In the present description a dihydrate is described which is a crystalline modification N, where the XRPD pattern, obtained with CuKa1 radiation, has specific peaks at positions ° 206.1 ± 0.2, 8.0 ± 0.2 and 12.0 ± 0.2; in certain cases, these are the three most significant peaks. The crystal modification N is also described, which has an XRPD pattern, obtained with CuKa1 radiation, with specific peaks at positions ° 206.1 ± 0.2, 8.0 ± 0.2 and 12.0 ± 0. , 2 and one or more of the characteristic peaks: 4.0 ± 0.2, 10.1 ± 0.2, 20.1 ± 0.2 and 21.0 ± 0.2. It is also described the crystalline modification N that has an XRPD pattern, obtained with CuKa1 radiation, with specific peaks at positions ° 206.1 ± 0.2, 8.0 ± 0.2, 12.0 ± 0 , 2, 4.0 ± 0.2, 10.1 ± 0.2, 20.1 ± 0.2 and 21.0 ± 0.2. In addition, the crystal modification N is described that has an XRPD pattern, obtained with CuKa1 radiation, with characteristic peaks at positions ° 206.1 ± 0.2, 8.0 ± 0.2, 12.0 ± 0, 2, 4.0 ± 0.2, 10.1 ± 0.2, 20.1 ± 0.2 and 21.0 ± 0.2, and one or more of 10.8 ± 0.2, 11.4 ± 0.2, 13.3 ± 0.2, 18.0 ± 0.2, 18.5 ± 0.2 and 19.7 ± 0.2. Furthermore, the crystal modification N having an XRPD pattern, obtained with CuKa1 radiation, is described, substantially as shown in Figure 6.

In embodiments where the dihydrate is the crystal modification E, the XRPD pattern, obtained with CuKa1 radiation, has specific peaks at the ° positions 206.1 ± 0.2, 12.1 ± 0.2 and 20.9 ± 0 ,2; In certain embodiments, these are the three most significant peaks. In a particular embodiment, the invention refers to the crystal modification E that has an XRPD pattern, obtained with CuKa1 radiation, with specific peaks at positions ° 206.1 ± 0.2, 12.1 ± 0.2 and 20.9 ± 0.2 and one or more of the characteristic peaks: 8.1 ± 0.2, 10.1 ± 0.2, 11.4 ± 0.2, 22.3 ± 0.2 and 22, 5 ± 0.2. In a more particular embodiment, the present invention refers to the crystal modification E that has an XRPD pattern, obtained with CuKa1 radiation, with specific peaks at positions ° 206.1 ± 0.2, 12.1 ± 0, 2, 20.9 ± 0.2, 8.1 ± 0.2, 10.1 ± 0.2, 11.4 ± 0.2, 22.3 ± 0.2, and 22.5 ± 0.2. In another embodiment, the present invention refers to the crystalline modification E that has an XRPD pattern, obtained with CuKa1 radiation, with characteristic peaks at positions ° 206.1 ± 0.2, 12.1 ± 0.2, 20.9 ± 0.2, 8.1 ± 0.2, 10.1 ± 0.2, 11.4 ± 0.2, 22.3 ± 0.2 and 22.5 ± 0.2, and one or more than 4.0 ± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 21.1 ± 0.2. In an even more particular embodiment, the invention relates to the crystal modification E having an XRPD pattern, obtained with CuKa1 radiation, substantially as shown in Figure 7.

The crystalline modifications described above may advantageously include one or more of the following characteristics, such as with respect to amorphous material: lower hygroscopicity, superior chemical stability, superior physical stability, improved processability into a formulation, reduced risk of residual solvent, Enhanced to manufacture from crude synthesized elobixibat and reproducible solubility. Many of these properties are highly relevant for compounds to be used in pharmaceutical preparations, where each formulation containing the active pharmaceutical ingredient must have the same pharmacological properties.

Elobixibat is an ileal bile acid transporter (ileal bile acid transporter inhibitor - IBAT). The ileal bile acid transporter (IBAT) is the main mechanism for reabsorption of bile acids from the GI tract. Partial or total blockage of this IBAT mechanism will result in a lower concentration of bile acids in the wall of the small intestine, portal vein, liver parenchyma, intrahepatic biliary tree, and extrahepatic biliary tree, including the gallbladder.

Diseases that can benefit from partial or total blockage of the IBAT mechanism may be those that have, as a primary pathophysiological defect, symptoms of excessive concentration of bile acids in serum and in the anterior organs.

Therefore, in another aspect, the invention further relates to the crystalline F, C, L and E modifications of elobixibat described in the present disclosure for use in therapy.

The crystalline modifications F, C, L and E of elobixibat described in the present description are useful in the prophylaxis or treatment of hypercholesterolemia, dyslipidemia, metabolic syndrome, obesity, disorders of fatty acid metabolism, disorders of glucose use, disorders involving insulin resistance, type 1 and type 2 diabetes mellitus, liver disease, diarrhea during therapy comprising an iBa T inhibitor compound, constipation including constipation chronic, p. g., functional constipation, including chronic idiopathic constipation (CIC) and constipation predominant irritable bowel syndrome (IBS-C). The treatment and prophylaxis of constipation is described in WO 2004/089350.

Other potential diseases to be treated with the elobixibat F, C, L and E crystal modifications described in the present disclosure are selected from the group consisting of liver parenchyma, inherited metabolic disorders of the liver, Byler syndrome, primary defects of bile synthesis. acid (bile acid - BA) such as cerebrotendinous xanthomatosis, secondary defects, such as Zellweger syndrome, neonatal hepatitis, cystic fibrosis (manifestations in the liver), ALGS (Alagilles syndrome), progressive familial intrahepatic cholestasis (progressive familial intrahepatic cholestasis - PFIC), autoimmune hepatitis, primary biliary cirrhosis (PBC), liver fibrosis, nonalcoholic fatty liver disease, NAFLD / NASH, portal hypertension, general cholestasis such as jaundice due to drugs or during pregnancy, cholestasis intrahepatic and extrahepatic such as inherited forms of cholestasis such as PFIC1, prima r and sclerosing cholangitis (primary sclerosing cholangitis - PSC), gallstones and choledocholithiasis, malignancy causing biliary tree obstruction, symptoms (scratching, pruritus) due to cholestasis / jaundice, pancreatitis, chronic autoimmune liver disease leading to progressive cholestasis, pruritus of cholestatic liver disease and pathologies associated with hyperlipidemic conditions.

Other diseases to be treated with elobixibat crystalline modifications F, C, L and E described in the present description are selected from the group consisting of liver disorders and related conditions, fatty liver, hepatic steatosis, non-alcoholic steatohepatitis (steatohepatitis non-alcoholic - NASH), alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, iron overload disorders, liver fibrosis, cirrhosis of the liver, hepatoma, viral hepatitis, and problems related to tumors and neoplasms of the liver, biliary tract and pancreas.

Therefore, in one embodiment, the invention relates to the crystalline F, C, L and E modifications of elobixibat described in the present disclosure for use in the treatment and / or prophylaxis of a disease or disorder as indicated above. .

Another aspect of the invention relates to a pharmaceutical composition comprising an effective amount of the crystalline modification F, C, L or E of elobixibat described in the present description, in association with a pharmaceutically acceptable diluent or carrier.

Yet another aspect of the invention relates to the use of crystalline modifications of elobixibat described in the present description in the preparation of a pharmaceutical composition, which comprises mixing the crystalline modification with a pharmaceutically acceptable diluent or carrier.

The pharmaceutical composition can also comprise at least one other active substance, such as an active substance selected from an IBAT inhibitor; an enteroendocrine peptide or enhancer thereof; a dipeptidyl peptidase-IV inhibitor; a biguanidine; an incretin mimetic; a thiazolidinone; a PPAR agonist; an HMG Co-A reductase inhibitor; a bile acid binder; a TGR5 receptor modulator; a member of the prostone class of compounds; a guanylate cyclase C agonist; a serotonin 5-HT4 agonist; or a pharmaceutically acceptable salt of any of these active substances. Examples of such combinations are further described in WO2012 / 064268.

The crystalline modifications of elobixibat will normally be administered to a warm-blooded animal at a unit dose within the range of 5 to 5000 mg per square meter of body area, i.e. approximately 0.1 to 100 mg / kg or 0, 01 to 50 mg / kg, and this normally provides a therapeutically effective dose. A unit dose form, such as a tablet or capsule, will usually contain from about 1 to 250 mg of active ingredient, such as from about 1 to 100 mg, or from about 5 to 50 mg, e.g. eg, about 1 to 20 mg. The daily dose can be administered as a single dose or divided into one, two, three or more unit doses. An orally administered daily dose of an IBAT inhibitor is preferably within 0.1 to 1000 mg, more preferably 1 to 100 mg, such as 5 to 15 mg.

The dosage required for therapeutic or prophylactic treatment will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors normally taken into account by the treating physician when determining the individual regimen and the appropriate dosage levels for a particular patient.

Definitions

The term "crystalline modification" refers to a crystalline solid phase of an organic compound. A crystalline modification can be a solvate or an ansolvate.

The term "solvate" refers to a crystalline solid phase of an organic compound, which has solvent molecules incorporated into its crystalline structure. A "hydrate" is a solvate where the solvent is water.

The term "suspension" refers to a saturated solution to which an excess of solid is added, thereby forming a mixture of solid and saturated solution, a "suspension".

As used herein, the terms "treatment", "treating" and "treating" refer to reversing, alleviating, delaying the presentation of, or inhibiting the progression of a disease or disorder, or one or more symptoms of the same, as described in the present description. In some embodiments, the treatment can be administered after one or more symptoms have developed. In other embodiments, the treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (eg, in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

When referring to a crystalline compound in the present description, preferably, the crystallinity as estimated by the X-ray powder diffraction data is greater than about 70%, such as greater than about 80%, particularly, greater to about 90%, more particularly, greater than about 95%. In embodiments of the invention, the degree of crystallinity as estimated by X-ray powder diffraction data is greater than about 98%, preferably greater than about 99%, where% crystallinity refers to the percentage by weight of the total sample mass that is crystalline.

Preferably, a crystalline modification according to the invention is substantially free of other crystalline modifications of the compound. Preferably, the elobixibat crystal modifications disclosed include less than, for example, 20%, 15%, 10%, 5%, 3%, or particularly less than 1% by weight of other elobixibat crystal modifications. Therefore, preferably, the solid phase purity of the described crystalline modifications of elobixibat is> 80%,> 85%,> 90%,> 95%,> 97%, or particularly> 99%.

The invention will now be described by way of the following examples, which do not limit the invention in any way.

Experimental methods

X-Ray Powder Diffraction Analysis (XRPD)

The dried samples were lightly ground in an agate mortar, if necessary, and then spread on a sample holder. Suspension samples were added to the sample holder as wet and were analyzed both wet and dry. XRPD data was collected on a cut silicon Zero Background Holder (ZBH) or on a porous alumina filter sample holder, using a PANalytical X'Pert Pro diffractometer, equipped with an X 'accelerator. or a PIXcel detector. The sample was centrifuged during analysis and Cu radiation was used. The following experimental setups were used:

Tube voltage and current: 40 kV, 50 mA

Wavelength alphal (CuKal): 1.5406 Á

Wavelength alpha2 (CuKa2): 1.5444 Á

Mean wavelength alpha1 and alpha2 (CuKa): 1.5418 Á

Starting angle [2 theta]: 1-4 °

Final angle [2 theta]: 30-40 °

Analysis time: 50 s (“1 min scan”), 125 s (“2 min scan”), 192 s (“3 min scan”), 397 s (“6 min scan”), 780 s (“13 min scan”), 1020 s (“17 min scan”), 4560 s (“1 h scan”)

Unless otherwise noted when calculating peak positions from the XRPD data, the data was first separated from the contribution of CuKa2 and then corrected against an internal standard (A ^ Os).

It is known in the art that an X-ray powder diffraction pattern can be obtained that has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation, or machine used). In particular, it is generally known that intensities in an XRPD standard can fluctuate depending on measurement conditions and sample preparation. For example, those skilled in the XRPD art will recognize that the relative intensities of the peaks can vary depending on the orientation of the sample under test and depending on the type and configuration of the instrument used. The person skilled in the art will further recognize that the position of the reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The flatness of the sample surface may also have a small effect. Therefore, a person skilled in the art will appreciate that the diffraction pattern presented in the present description is not to be construed as absolute and any crystalline form that provides a powder diffraction pattern substantially identical to those described in the present description is within the scope of this description (for For more information, see R. Jenkins and RL Snyder, "Introduction to X-ray powder diffractometry", John Wiley & Sons, 1996).

Dynamic Vapor Sorption (DVS)

Approximately 2-16 mg of the sample was weighed into a metal container, which was then freed of static electricity. The metal receptacle was placed on a Surface Measurements System Ltd. DVS Advantage instrument. The sample was subjected to two consecutive sorption-desorption cycles, each operating from 0-95-0% relative humidity (% RH). A cycle consisted of 21 stages, those between 0-90% RH were taken at 10% RH each. In each stage the following equilibrium criteria were used: dm / dt for 5 minutes <0.002% and the minimum and maximum time in each stage were 10 and 360 min, respectively.

The starting material 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (W - {(R) -1'-phenyl-1 '- [W- (t-butoxycarbonylmethyl) carbamoyl] methyl} carbamoylmethoxy) -2,3,4,5-tetrahydro-1,5-benzothiazepine can be prepared as described in WO02 / 50051.

Examples

Preparation of form A monohydrate

Form A monohydrate can be prepared according to the methods described in PCT application number PCT / EP2014 / 058432, filed April 25, 2014, referred to herein as crystalline modification IV. Briefly, Form A can be prepared by mixing 100 mg of any dry solid Elobixibat material with 2 ml of ethanol, in a closed container for one week. The solid is then isolated and dried under vacuum at elevated temperature until the ethanol has dried. Finally, the solid is exposed to humid air at room temperature until the highly crystalline monohydrate form A has formed.

Preparation of MIBK solvate form G and anhydrate form F

102 mg of Elobixibat form A monohydrate was dissolved in 0.5 ml of methyl isobutyl ketone (MIBK) in a 10 ml test tube at 60 ° C. Then n-heptane was added in 0.1 ml portions over a period of 2 hours. When 0.6 ml of n-heptane was added, precipitation occurred. The container was then allowed to stir for 4 days until a thick white suspension formed. The vessel was cooled to 21 22 ° C and a sample was then removed from the suspension with a Pasteur pipette and placed in a cut silicon zero background holder (ZBH). The wet sample was analyzed with XRPD, which showed that it consisted of the G form of MIBK solvate (Fig. 8).

A sample of the suspension was dried overnight at 100 ° C under vacuum and then analyzed with XRPD. This showed that it was now the anhydrate F form (Fig. 1).

Preparation of Form H Ethyl Acetate Solvate and Form F Anhydrate

441 mg of Elobixibat form A monohydrate, 0.6 ml of ethyl acetate and 0.6 ml of n-heptane were added to a 10 ml test tube. A stirring magnet was added, the container was closed, and then stirred for 2 days at 62 ° C. The suspension was sampled on a hot (60 ° C) alumina XRPD porous substrate and analyzed with XRPD, showing that it consisted of form H of ethyl acetate solvate (Fig. 9).

A sample of the solid was dried at 100 ° C under dry nitrogen gas and then analyzed with XRPD. It consisted of the anhydrate F form (Fig. 2). Alternatively, the sample was dried at 100 ° C under vacuum for 7.5 hours.

The DVS data for crystal modification F is provided in Fig. 10. As can be seen, moisture absorption is a linear function of% RH.

Preparation of form E dihydrate and form C anhydrate

111 mg of Elobixibat form A monohydrate was weighed into a 10 ml test tube. A magnetic flea and 2.0 ml of a 50:50% v / v acetone: water mixture were added. This produced a gel-like material, which had to be shaken by hand and shaken vigorously for a couple of minutes, before the test tube could be closed and put on magnetic stirring, at 21-22 ° C. Two days later, a sample of the white suspension was removed with a Pasteur pipette and placed in a cut silicon zero background holder (ZBH). The wet sample was analyzed with XRPD, which showed that it consisted of the E form dihydrate (Fig. 7).

About half of the contents of the test tube were poured into a crystallization vessel which was then vacuum dried for 2 hours at 60 ° C. This sample was then analyzed with XRPD, which showed that it consisted of the anhydrate C form (Fig. 3).

The DVS data for the transformation between crystalline modifications C and E are shown in Fig. 11. The lower curves, showing a significant change in humidity between 60-70% RH, indicating the phase change of modification C to E, are the two sorption cycles. The upper curves, showing the change in humidity for the reverse phase transition between 20-10% RH, are the desorption curves. The hysteresis between the sorption and desorption curves is due to kinetic reasons. The theoretical amount of moisture for a dihydrate is 4.9% w / w which fits well with the four curves that coincide around 5% w / w.

Preparation of form D solvate and form C anhydrate

95 mg of Elobixibat form A monohydrate was weighed into a 10 ml test tube. A magnetic flea and 2.0 ml of ethyl acetate were added. This produced a suspension, which was placed under magnetic stirring, at 21-22 ° C. Two days later, a sample of the white suspension was removed with a Pasteur pipette and placed in a cut silicon zero background holder (ZBH). The wet sample was analyzed with XRPD, which showed that it consisted of the D-solvate form (Fig. 12). The XRPD sample was stored for 3 days at 21-22 ° C and 30% relative humidity and then analyzed again with XRPD. It now contained form C anhydrate (Fig. 4).

Preparation of acetonitrile solvate form M and anhydrate form L

99 mg of Elobixibat form A monohydrate were weighed into a 10 mL + l test tube. A magnetic flea and 2.0 ml of acetonitrile were added. This dissolved the solid, but it rapidly re-precipitated, thus forming a suspension. The test tube was closed and placed under magnetic stirring, at 21-22 ° C. Two days later, a sample of the white suspension was removed with a Pasteur pipette and placed in a cut silicon zero background holder (ZBH). The wet sample was analyzed with XRPD, which showed that it consisted of the M form of acetonitrile solvate (Fig. 13).

The suspension was poured into a crystallization vessel and allowed to dry in open laboratory air. Then it was dried for 6 hours under vacuum and 100 ° C. After cooling in a dry silica gel desiccator, it was analyzed with XRPD. It consisted of the anhydrate L form (Fig. 5).

Reference example: Preparation of form N dihydrate

A flat sample of the anhydrate L-form was moistened by adding drops of water to it. Due to the hydrophobic properties of the solid, the droplets were very slowly absorbed by the solid. When the sample had absorbed the water, it was analyzed with XRPD and then consisted of the N-dihydrate form (Fig. 6).

The DVS data for the transformation between the L and N crystalline modifications are provided in Fig. 14. The lower curves, showing a significant change in humidity between 40-50% RH, indicating the phase change of modification L to N are the two sorption cycles. The upper curves, showing the change in humidity for the reverse phase transition between 20-10% RH, are the desorption curves. The hysteresis between the sorption and desorption curves is due to kinetic reasons. The theoretical amount of moisture for a dihydrate is 4.9% w / w which fits well with the four curves that coincide around 5% w / w.

Reference example: Preparation of form N dihydrate directly from a suspension

30 mg of elobixibat was weighed into a 1.0 ml test tube. A magnetic flea and 0.5 ml of a 50:50% v / v 2-propanol: water mixture were added. The test tube was closed and placed under magnetic stirring, at 50C. A week later a sample was removed from the white suspension with a Pasteur pipette and placed in a porous corundum sample holder. The wet sample was analyzed with XRPD, which was consistent with that of the N dihydrate form.

Conclusions

A summary of the solid state behavior of elobixibat described in this application is found in Fig. 15

Claims (13)

1. Crystalline anhydrate F of elobixibat, which has an XRPD pattern, obtained with CuKal radiation, with peaks at positions ° 296.1 ± 0.2 and 5.9 ± 0.2. 2. The anhydrate of claim 1, having an XRPD pattern, obtained with CuKa1 radiation, as shown in Fig. 1 or Fig. 2. 3. Crystalline anhydrate C of elobixibat, which has an XRPD pattern, obtained with CuKa1 radiation, with peaks at the ° 2912.4 ± 0.2 and 5.8 ± 0.2 positions. 4. The anhydrate of claim 3, having an XRPD pattern, obtained with CuKa1 radiation, as shown in Fig. 3 or Fig. 4. 5. Crystalline anhydrate L of elobixibat, which has an XRPD pattern, obtained with CuKa1 radiation, with peaks at the ° positions 296.4 ± 0.2 and 12.7 ± 0.2. 6. The anhydrate of claim 5, having an XRPD pattern, obtained with CuKa1 radiation, as shown in Fig. 5. 7. Elobixibat crystalline dihydrate E, which has an XRPD pattern, obtained with CuKa1 radiation, with the most significant peaks at the ° positions 296.1 ± 0.2, 12.1 ± 0.2 and 20.9 ± 0.2. 8. The dihydrate of claim 7, having an XRPD pattern, obtained with CuKa1 radiation, as shown in Fig. 7. 9. The crystalline elobixibat anhydrate or crystalline dihydrate of any of claims 1-8, for use in therapy. 10. A pharmaceutical composition comprising the crystalline elobixibat anhydrate or crystalline dihydrate of any of claims 1-8, together with a pharmaceutically acceptable diluent or carrier. 11. The crystalline anhydrate or crystalline dihydrate of elobixibat of any of claims 1-8, for use in the treatment or prophylaxis of a disease selected from the group consisting of hypercholesterolemia, dyslipidemia, metabolic syndrome, obesity, metabolic disorders of fatty acids, glucose use disorders, disorders involving insulin resistance, type 1 and type 2 diabetes mellitus, liver diseases, diarrhea during therapy comprising an IBAT inhibitor compound, constipation including chronic constipation , p. eg, functional constipation, including chronic constipation and constipation predominant irritable bowel syndrome (IBS-C). 12. The crystalline anhydrate or crystalline dihydrate of elobixibat of any of claims 1-8, for use in the treatment or prophylaxis of a disease selected from the group consisting of liver parenchyma, inherited metabolic disorders of the liver, Byler syndrome, Primary defects of bile acid synthesis (bile acid - BA) such as cerebrotendinous xanthomatosis, secondary defects such as Zellweger syndrome, neonatal hepatitis, cystic fibrosis (manifestations in the liver), ALGS (Alagilles syndrome), progressive intrahepatic familial cholestasis (progressive familial intrahepatic cholestasis - PFIC), autoimmune hepatitis, primary biliary cirrhosis (primary biliary cirrhosis - PBC), liver fibrosis, nonalcoholic fatty liver disease, NAFLD / NASH, portal hypertension, general cholestasis, such as in jaundice due to drugs or during pregnancy, intrahepatic and extrahepatic cholestasis such as inherited forms of cholestasis such as PFIC1, primary sclerosing cholangitis (primary sclerosing cholangitis - PSC), gallstones and choledocholithiasis, malignancy causing biliary tree obstruction, symptoms (scratching, pruritus) due to cholestasis / jaundice, pancreatitis, chronic autoimmune liver disease leading progressive cholestasis, pruritus of cholestatic liver disease and pathologies associated with hyperlipidemic conditions. 13. The crystalline anhydrate or crystalline dihydrate of elobixibat of any of claims 1-8, for use in the treatment or prophylaxis of a disease selected from the group consisting of liver disorders and related conditions, fatty liver, steatosis liver, non-alcoholic steatohepatitis (nonalcoholic steatohepatitis - NASH), alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, iron overload disorders, liver fibrosis, liver cirrhosis, hepatoma, viral hepatitis and related problems with tumors and neoplasms of the liver, biliary tract and pancreas.